Antimicrobial Peptoids Show Potent Antifungal Activity against Candidozyma (Candida) auris In Vivo and Broad-Spectrum Activity In Vitro against Other Candida Species

Abstract Invasive candidiasis is a serious fungal infection caused by Candida species that can enter the bloodstream and affect major organs, particularly in immunocompromised patients. Development of resistance to standard antifungal therapies, especially with C. auris, has become a major public health issue. While antimicrobial peptides such as the human cathelicidin, LL-37, could represent a possible therapeutic strategy, they are often inactivated when delivered systemically. One alternative therapeutic strategy is antimicrobial peptoids. We studied in vitro activity of three peptoid compounds, oligomers of N-substituted glycines, which mimic the activity of LL-37. Our aim was to establish these peptoid compounds as a potential treatment of invasive candidiasis and compare them to LL-37′s antifungal activity. In vitro, LL-37 did not exhibit antifungal activity (MIC > 64) against all C. auris strains and three species of Candida. In contrast, three peptoids were tested against ten C. auris strains and six other Candida species and showed good activity. MICs measured as low as 4 μg/mL for TM5 against C. auris strain 381. Mechanistic studies using TEM and fluorescent confocal microscopy of peptoids against C. auris clinical isolates showed membrane disruption and consolidation of organelles. Peptoids TM4 and TM5 showed strong synergistic effects with fluconazole and caspofungin, and amphotericin B. Serial daily passage of TM4 and TM5 at sub-MIC concentrations showed no resistance developing for up to 3 weeks. Fungicidal kinetics revealed complete killing of fungal colonies after around 1 h. A systemic candidiasis mouse model treated subcutaneously with TM5 3 h after C. auris infection resulted in clearing of infection, indicated by colony forming units (cfu) per gram of kidney, at 24 h with the 5 mg/kg dose. This demonstrates that antimicrobial peptoids are active systemically and have potential to be an antifungal treatment for candidemia, particularly as an alternative therapy for resistant strains.